A comprehensive program is proposed for study of the structure, function and genetic control of a series of inadequately characterized human plasma proteins, principally Alpha-glycoproteins and Beta-glycoproteins and certain blood coagulation factors. Some have identified function and clinical significance and others not, but in most cases little is known about their structure. Emphasis will be on determination of the amino acid sequence, disulfide bonding pattern, localization and kind of carbohydrate groups, and the combining sites of ligands such as metal ions and heme. Correlation of function and structure will be sought and interrelationships with other plasma proteins will be investigated. Some correlations will be done in cooperation with other groups studying changes in plasma proteins in disease, their genetic polymorphism and variation, their metabolism and membrane uptake, and their three-dimensional structure. We have already determined the complete primary structure of human ceruloplasmin, hemopexin, Beta2-glycoprotein I, and leucine-rich Alpha2-glycoprotein. The sequence of Alpha1B blycoprotein is almost complete and other proteins are being investigated. Now, effort is being directed to study of the copper-binding sites and oxidase activity of ceruloplasmin, and its homology to blood coagulation Factors V and VIII; also, the heme-binding and hepatocyte receptor sites of hemopexin are being studied in several species. A parallel study is under way on histidine-rich Alpha2-glycoprotein, (autorosette inhibition factor), which binds metals and many hemes. Emphasis will be given to the postsynthetic mechanisms by which many plasma proteins are activated or proteolytically degraded. An automated tandem HPLC system has been developed for use in peptide mapping of very large proteins. It is being applied to ceruloplasmin from Wilson disease and to genetic variants of serum albumin. The goals are to make a major contribution to knowledge about human plasma proteins, to integrate information gained from in vitro study with in vivo function, and to focus attention on the characterization, quantitation, and clinical significance of this group of proteins from human blood plasma. The methods to be used include amino acid and carbohydrate analysis, amino acid sequence analysis, an automated two-dimensional HPLC system, immunochemical and physicochemical characterization, computerized analysis of amino acid sequence homologies and of parameters of secondary structure, nuclear magnetic resonance spectroscopy, circular dichroism, and other procedures for structureal study of protein and carbohydrates.